Targeted alpha therapy
Alpha therapy uses a heavier type of radioactive particle that travels only a few cell widths but hits much harder, aimed at cancer cells that have stopped responding to the gentler beta-particle treatments.
Overview
Targeted alpha therapy (TAT) conjugates an alpha-emitting radionuclide, most often actinium-225, to the same PSMA or somatostatin-receptor ligands used in beta radioligand therapy. Alpha particles have a short tissue range (tens of micrometres, a few cell diameters) but a much higher linear energy transfer than beta particles, so they cause dense, largely non-repairable double-strand DNA breaks. Radium-223 (Alpharadin), an alpha-emitting bone-seeking agent, was the first alpha emitter approved in oncology, on the basis of the ALSYMPCA trial (improved overall survival and delayed skeletal-related events in bone-predominant mCRPC).
For tumour-targeted alpha therapy, 225Ac-PSMA agents (including Fusion Pharmaceuticals' FPI-2265 in the AlphaBreak programme, and RayzeBio/BMS's RYZ101, 225Ac-DOTATATE, for neuroendocrine tumours) are in phase 1/2 development, largely in patients who progressed on or are refractory to lutetium-177 therapy. A 2026 systematic review and meta-analysis (Belabaci et al., Eur J Nucl Med Mol Imaging 2026) assessed combined 225Ac/177Lu-PSMA therapy but the field still lacks randomised phase 3 evidence for any alpha-PSMA agent.
The defining unsolved problem is supply, not biology: global 225Ac production is estimated at roughly 63 GBq (1.7 Ci) per year, sufficient for only about 100-200 patients annually, against an estimated clinical and trial demand of around 185 GBq/year and rising (Alpha Atlas / IAEA TECDOC-2057, 2024). Production depends on a handful of 229Th generators (Oak Ridge National Laboratory, the EU Joint Research Centre in Karlsruhe, and Russia's IPPE) or on cyclotron irradiation of 226Ra, and the IAEA's Global Radium-226 Management Initiative is recovering legacy radium sources from around 80 countries as an alternative feedstock. Xerostomia (salivary gland uptake) and dosimetric uncertainty are the main clinical limitations reported so far.
Notes
top- Global 225Ac supply (~63 GBq/year) covers only about 100-200 patient treatments a year against an estimated demand of ~185 GBq/year and rising (IAEA TECDOC-2057, 2024).
- No alpha-PSMA agent has randomised phase 3 evidence yet; current clinical use is investigational or salvage after lutetium-177.
- The IAEA's Global Radium-226 Management Initiative is recovering legacy radium sources from roughly 80 countries as feedstock for 225Ac, a genuinely new supply route rather than incremental reactor capacity.